Retinoic Acid Receptor β Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease

In alcohol-associated liver disease (ALD), hepatic reductions in vitamin A and perturbations in vitamin A metabolism are common. However, the roles that the vitamin A receptors, termed retinoic acid receptors (RARs), may have in preventing the pathophysiology of ALD remains unclear. Our prior data i...

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Published inInternational journal of molecular sciences Vol. 24; no. 15; p. 12035
Main Authors Melis, Marta, Trasino, Steven E, Tang, Xiao-Han, Rappa, Andrew, Zhang, Tuo, Qin, Lihui, Gudas, Lorraine J
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 27.07.2023
MDPI
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Summary:In alcohol-associated liver disease (ALD), hepatic reductions in vitamin A and perturbations in vitamin A metabolism are common. However, the roles that the vitamin A receptors, termed retinoic acid receptors (RARs), may have in preventing the pathophysiology of ALD remains unclear. Our prior data indicate that a RARβ agonist limits the pathology of alcohol-related liver disease. Thus, we generated liver-specific AlbCre-RARβ knockout (BKO) mice and compared them to wild type (WT) mice in an early ALD model. Both strains showed similar blood ethanol concentrations and ETOH-metabolizing enzymes. However, the livers of pair-fed-BKO and ETOH-BKO mice developed higher levels of steatosis and triglycerides than pair-fed-WT and ETOH-WT mice. The increased hepatic steatosis observed in the pair-fed-BKO and ETOH-BKO mice was associated with higher lipid synthesis/trafficking transcripts and lower beta-oxidation transcripts. ETOH-BKO mice also exhibited a higher integrated stress response (ISR) signature, including higher transcript and protein levels of ATF4 and its target, 4-EBP1. In human hepatocytes (HepG2) that lack RARβ (RARβ-KO), ETOH treatments resulted in greater reactive oxygen species compared to their parental cells. Notably, even without ETOH, ATF4 and 4-EBP1 protein levels were higher in the RARβ-KO cells than in their parental cells. These 4-EBP1 increases were greatly attenuated in cultured ATF4-deficient and RARβ/ATF4-deficient HepG2, suggesting that RARβ is a crucial negative regulator of 4-EBP1 through ATF4 in cultured hepatocytes. Here, we identify RARβ as a negative regulator of lipid metabolism and cellular stress in ALD.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241512035